Citations

ABSTRACT Insulin resistance causes diminished glucose uptake in similar regions of the brain in Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2). Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)‐serine‐type 1 insulin receptor substrate (IRS‐1) and less P‐tyrosine‐IRS‐1. Plasma exosomes enriched for neural sources by immunoabsorption were obtained once from 26 patients with AD, 20 patients with DM2, 16 patients with frontotemporal dementia (FTD), and matched case control subjects. At 2 time points, they were obtained from 22 others when cognitively normal and 1 to 10 yr later when diagnosed with AD. Mean exosomal levels of extracted P‐serine 312‐IRS‐1 and P‐pan‐tyrosine‐IRS‐1 by ELISA and the ratio of P‐serine 312‐IRS‐1 to P‐pan‐tyrosine‐IRS‐1 (insulin resistance factor, R) for AD and DM2 and P‐serine 312‐IRS‐1 and R for FTD were significantly different from those for case control subjects. The levels of R for AD were significandy higher than those for DM2 or FTD. Stepwise discriminant modeling showed correct classification of 100% of patients with AD, 97.5% of patients with DM2, and 84% of patients with FTD. In longitudinal studies of 22 patients with AD, exosomal levels of P‐serine 312‐IRS‐1, P‐pan‐tyrosine‐IRS‐1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects. Insulin resistance reflected in R values from this blood test is higher for patients with AD, DM2, and FTD than case control subjects; higher for patients with AD than patients with DM2 or FTD; and accurately predicts development of AD up to 10 yr prior to clinical onset.—Kapogiannis, D., Boxer, A., Schwartz, J. B., Abner, E. L., Biragyn, A., Masharani, U., Frassetto, L., Petersen, R. C., Miller, B. L., Goetzl, E. J. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural‐derived blood exosomes of preclinical Alzheimer's disease. FASEB J . 29, 589‐596 (2015). www.fasebj.org

Abstract Background Proteins pathogenic in Alzheimer's disease (AD) were extracted from neurally derived blood exosomes and quantified to develop biomarkers for the staging of sporadic AD. Methods Blood exosomes obtained at one time‐point from patients with AD (n = 57) or frontotemporal dementia (FTD) (n = 16), and at two time‐points from others (n = 24) when cognitively normal and 1 to 10 years later when diagnosed with AD were enriched for neural sources by immunoabsorption. AD‐pathogenic exosomal proteins were extracted and quantified by enzyme‐linked immunosorbent assays. Results Mean exosomal levels of total tau, P‐T181‐tau, P‐S396‐tau, and amyloid β 1–42 (Aβ1–42) for AD and levels of P‐T181‐tau and Aβ1–42 for FTD were significantly higher than for case‐controls. Step‐wise discriminant modeling incorporated P‐T181‐tau, P‐S396‐tau, and Aβ1–42 in AD, but only P‐T181‐tau in FTD. Classification of 96.4% of AD patients and 87.5% of FTD patients was correct. In 24 AD patients, exosomal levels of P‐S396‐tau, P‐T181‐tau, and Aβ1–42 were significantly higher than for controls both 1 to 10 years before and when diagnosed with AD. Conclusions Levels of P‐S396‐tau, P‐T181‐tau, and Aβ1–42 in extracts of neurally derived blood exosomes predict the development of AD up to 10 years before clinical onset.

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.